Interstitial cystitis (IC) is a chronic inflammation or irritation of the urinary bladder wall that is estimated to affect 700,000 people (approximately 90% female) in the United States. The primary symptoms of IC are urinary urgency, frequency, and often-severe pelvic and perineal pain. The similarity of the symptoms of IC with other bladder diseases, such as urinary tract infections (UTI), urethritis, urethral syndrome, trigonitis, prostatitis, dysuria, and nocturia has caused difficulty in the diagnosis of the disease. After other similar bladder diseases are ruled out and a cystoscopic examination of the bladder wall reveals characteristic signs of IC, including small petechial hemorrhages or larger Hunner's Ulcers, IC is usually diagnosed.
The etiology and pathogenesis of the transmural inflammation in IC are unclear. The diagnosis is one of exclusion, and the treatment is usually empiric. The symptoms of IC arise from a defect in the glycosaminoglycan (GAG) component of the mucin layer that covers and protects the bladder urothelium. A deficiency of this layer is thought to cause IC.
The GAG hypothesis is the basis for treating interstitial cystitis with glycosaminoglycan “replacements,” such as sodium pentosan polysulfate and heparin or hyaluronic acid administered intravesically. Irritating substances in the urine may leak through the urothelium, causing inflammation, tissue irritation and injury, mast cell degranulation and sensory nerve depolarization, which result in the urinary urgency, frequency and pain of interstitial cystitis. Glycosaminoglycans are highly hydrophilic and protective. They maintain a stable layer of water between the urothelium and the bladder lumen, and prevent adhesion to and invasion of the urothelium by bacteria, microcrystals, ions, proteins and other substances in the urine.
Currently there is no permanent cure for IC in the majority of patients. Treatment of IC with drug therapy has been proven to be the most effective means of alleviating symptoms. Oral medications for IC include bladder-coating agents, antidepressants, antihistamines, antispasmodics, and anesthetics. The effectiveness of oral medications is limited by the circulating concentration of the drug in the blood stream. To address this limitation, many IC patients elect to undergo a procedure called urinary bladder instillation, in which a therapeutic solution is pumped into the bladder through a urethral catheter.
Proposed treatments include pentosan polysulfate, anti-inflammatory or immunosuppressant therapy, muscle relaxants, anti-histamines, and analgesics. Of these, only pentosan polysulfate (Elmiron) has been specifically approved by the FDA for IC. None of the proposed therapies, including pentosan polysulfate, which may take up to 6 months to work, is universally accepted or universally efficacious. There is no cure and no effective treatment that works for everyone; treatments are intended to relieve symptoms. Bladder distension, which is often part of diagnosis, is first line, because this treatment may ameliorate symptoms. Surgery is considered only in last resort and does not offer significant long term benefit.
The related conditions of irritable bowel syndrome and ulcerative colitis are also difficult to treat with existing therapeutic agents. These are nonspecific inflammatory diseases of the colon of unknown cause, characterized by diarrhea with discharge of mucus and blood, cramping abdominal pain, and inflammation and edema of the mucous membrane with patches of ulceration.
Without meaning to be limited by theory, we believe that a unique breadth of receptor sites can be blocked by compounds of the present invention. Few, if any, of the known inhibitors of inflammatory disease embody all of the following sites of activity in a single molecule: inhibition of 1) leukotriene synthesis, 2) leukotriene D-4 receptors, 3) leukotriene E-4 receptors, 4) cAMP PDE III, 5) cAMP PDE IV, 6) synthesis of thromboxane A-2, 7) eosinophil migration and 8) lymphocyte migration. The above mechanisms are involved and cooperate in different degrees and with different specificities among the wide variety of cells interacting in the so-called “inflammatory cascade,” to produce a fission-like result. By blocking a wide variety of action sites, compounds 1 and 2 are expected to be effective for a wide array of illnesses that fall under the umbrella of “inflammatory diseases.”
Since the biochemical messengers of inflammation cause an “explosive” type of reaction in the tissues, we suggest that the additive effects of the broad sites of action of the present compounds will result in high “multiplier” effects in amelioration of the urinary condition interstitial cystitis, as well as inflammatory disorders of the gastrointestinal tract, especially irritable bowel syndrome and ulcerative colitis.